Giron-Michel Julien, Giuliani Massimo, Fogli Manuela, Brouty-Boyé Danièle, Ferrini Silvano, Baychelier Florence, Eid Pierre, Lebousse-Kerdilès Caroline, Durali Deniz, Biassoni Roberto, Charpentier Bernard, Vasquez Aimé, Chouaib Salem, Caignard Anne, Moretta Lorenzo, Azzarone Bruno
Medicina Istituto Gaslini and the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Blood. 2005 Oct 1;106(7):2302-10. doi: 10.1182/blood-2005-01-0064. Epub 2005 Jun 23.
Membrane-bound and soluble interleukin-15 (IL-15)/IL-15 receptor alpha (Ralpha) complexes trigger differential transcription factor activation and functions on human hematopoietic progenitors. Indeed, human spleen myofibroblasts (SMFs) are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb [membrane-bound]-IL-15), based on the association of an endogenous IL-15/IL-15Ralpha complex with the IL-15Rbetagamma c chains. SMFmb-IL-15 (1) induces lineage-specific signaling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors; (2) triggers survival and proliferation of leukemic progenitors expressing low-affinity IL-15R (M07Sb cells); (3) causes only an antiapoptotic effect on leukemic cells expressing high-affinity receptors (TF1beta cells). This behavior is likely due to the IL-15Ralpha chain present on these cells that interact with the SMFmb-IL-15, inhibiting signal transducer and transcriptional activator 5 (STAT5) activation. On the other hand, the soluble IL-15/IL-15Ralpha complex (hyper IL-15) displays a dominant pattern of action, activating only those cells expressing low-affinity IL-15R (IL-15Rbetagamma c). Thus, hyper IL-15 induces antiapoptotic effects on M075b cells and the up-regulation of STAT6 activation on adult peripheral blood (PB) pre-natural killer (NK) committed progenitors. The latter effect using 100-fold concentrations of recombinant (r)-IL-15. In conclusion, SMFmb-IL-15 and soluble IL-15Ralpha/IL-15 complexes seem to play a pivotal role in the control of the survival, proliferation and differentiation of both normal and leukemic circulating progenitors, highlighting new functions of IL-15 and of IL-15Ralpha.
膜结合型和可溶性白细胞介素-15（IL-15）/白细胞介素-15受体α（Rα）复合物可引发不同的转录因子激活，并作用于人类造血祖细胞。实际上，人脾肌成纤维细胞（SMF）具有一种新型的IL-15反式呈递机制（SMFmb [膜结合型]-IL-15），其基础是内源性IL-15/IL-15Rα复合物与IL-15Rβγc链的结合。SMFmb-IL-15（l）在未致敏和定向的正常祖细胞中诱导不同于可溶性IL-15所控制的谱系特异性信号通路；（2）触发表达低亲和力IL-15R的白血病祖细胞（M07Sb细胞）的存活和增殖；（3）对表达高亲和力受体的白血病细胞（TF1β细胞）仅产生抗凋亡作用。这种行为可能是由于这些细胞上存在的IL-15Rα链与SMFmb-IL-15相互作用，抑制了信号转导子和转录激活子5（STAT5）的激活。另一方面，可溶性IL-15/IL-15Rα复合物（超IL-15）表现出一种主导的作用模式，仅激活那些表达低亲和力IL-15R（IL-15Rβγc）的细胞。因此，超IL-15对M075b细胞诱导抗凋亡作用，并上调成人外周血（PB）天然杀伤（NK）定向祖细胞上STAT6的激活。后一种作用使用的重组（r）-IL-15浓度为前者的100倍。总之，SMFmb-IL-15和可溶性IL-15Rα/IL-15复合物似乎在正常和白血病循环祖细胞的存活、增殖和分化控制中起关键作用，突出了IL-15和IL-15Rα的新功能。
